HSV-1 is an important human pathogen, with a global prevalence of ~67% according to World Health Organization. In immunocompromised people, such as those with advanced HIV infection, HSV-1 cause more severe symptoms such as encephalitis or keratitis though rarely. Mother-to-infant transmission can occur, though rarely, estimated 1 out of every 10,000 births globally, but can lead to lasting neurologic disability or death. The mosquito-borne Chikungunya virus (CHIKV) of the Togaviridae family is re-emerging as a significant public health threat world-wide. CHIKV causes acute and chronic crippling arthralgia and long-term neurological disorders. The cumulative cases are over 1.8 million, with 436 deaths directly or indirectly related to CHIKV, in Americas since its invasion into the Caribbean in late 2013. This project investigates the physiological roles of a family of poorly understood genes, UBXNs, in controlling HSV-1 and CHIKV infection and disease pathogenesis in mice via genetic, molecular biological, biochemical and immunological approaches, and may ultimately contribute to development of vaccines and therapeutics. We will first examine the changes in disease pathogenesis and antiviral immune responses of gene deficient animals and cells. We will then understand how UBXNs regulate the innate immune system, specifically the stimulator of interferon genes (STING) pathway, to limit viral infection. STING senses cyclic GMP-AMP (cGAMP), a second messenger that is rapidly synthesized by cGAMP synthase (cGAS) in response to viral DNA, and then induces expression of type I IFNs and other antiviral molecules. Our study with West Nile virus (WNV) and other recent studies consistently demonstrate that STING is also important for the control of RNA virus infection in mouse models. The underlying molecular mechanism, however, remain largely unclear. At the end of this project, we hope to address a gap in our knowledge and understanding of the role of STING in innate immunity to RNA viruses and UBXN3B in regulation of STING-mediated innate antiviral immune response, and increase our knowledge in the host immune responses to human viruses of medical significance.